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Obesity is a risk factor for endometrial hyperplasia (EH), endometrial intraepithelial neoplasia (EIN), and early type 1 endometrial cancer (EC) in 70%–90% of patients and is often a significant contributor to overall morbidity and mortality due to comorbidities. In 2011, bariatric surgery (BS) with lifestyle modification was identified as an intervention for reduction in overall mortality as well as risk for gynecologic cancers (Tsui et al., 2021). Our aim was to assess awareness of obesity as a risk factor and understanding of BS in an underinsured obese patient population with EC or EH. This IRB-approved survey was distributed to patients with type I EC or EH within the past 5 years and a BMI >30. Questions addressed demographics, health habits, cancer and obesity awareness, as well as benefits and concerns about undergoing BS. Information was provided about dietary requirements after BS, and then interest in BS was surveyed. 61.2% of surveyed patients were interested in bariatric surgery for weight loss after receiving education about the procedure. Interest in bariatric surgery was correlated with higher BMI, higher ideal and comfortable weight loss in pounds and higher estimated weight loss that could be obtained with bariatric surgery. Additionally, patients who were interested in BS had better understanding of the risks of obesity with cancer overall. Obese patients with history of EC/EIN/EH are aware of hazards associated with excess weight and understand the relationship between EC/EIN/EH diagnosis and obesity, and overall are very interested in BS as a modality to improve their health. • Low resource endometrial cancer and precancer patients understand that excess weight increases their risk for cancer. • More than half of endometrial cancer or precancer patients are interested in bariatric surgery after education about diet. • Endometrial cancer patients not interested in weight loss surgery are concerned about cost, recovery and complications. [ABSTRACT FROM AUTHOR]

Background: The majority of women with endometrial cancer (EC) present at an early stage with an associated 5-year survival rate of >90%. High rates of early detection are attributed to warning symptoms; however, the prevalence of such symptoms has not been well defined. Methods: A case-control study was conducted assessing the prevalence of symptoms in EC patients at a large cancer center compared with healthy controls. Controls included patients seen for an annual gynecologic care visit (AV) or for a gynecological problem-based visit (PV). A self-administered questionnaire was given to all participants addressing EC-associated symptoms, at the time of initial clinic visit. Odds ratios (ORs) were used to compare prevalence of symptoms between EC cases and controls. Logistic regression was used to determine the impact of menopausal status and obesity on symptom prevalence. Results: The cases ( n = 75) were significantly older than the AV ( n = 203) and PV ( n = 151) controls (59.7 vs. 49.8 vs. 51.0 years, p < 0.01), had a higher body mass index (35.5 vs. 29.4 vs. 30.9 kg/m2, p < 0.01), and were more likely to be postmenopausal (76% vs. 53.7% vs. 52.0%, p < 0.01). The cases were more likely to report postmenopausal bleeding (OR = 32.99 and 5.83, p < 0.01) and abnormal vaginal discharge (OR = 8.8 and 3.3, p < 0.01) compared with the AV and PV groups. Overall, 55.4% of cases reported abnormal vaginal discharge. Conclusions: Symptoms of both postmenopausal bleeding and abnormal vaginal discharge were significantly higher in EC compared with controls. The presence of such symptoms should raise concern for malignant disease and prompt immediate gynecological evaluation. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The aims of this study were to implement a patient-administered checklist designed to identify endometrial cancer patients at elevated risk for Lynch syndrome; measure subsequent genetic counseling and testing; and identify differences between those who attended genetic counseling and those who did not. Methods: We developed a 4-item yes/no checklist of personal and family history risk factors for Lynch syndrome-associated endometrial cancer and recommended referral for genetic counseling for patients meeting any of the criteria. Retrospective chart review was performed to determine subsequent genetic counseling and testing outcomes over a 15month period. Results: 6/387 (1.6%) of endometrial cancer patients tested positive for a Lynch syndrome mutation. 4/24 (17%) of endometrial cancer patients who met referral criteria and attended genetic counseling tested positive. 38/70 (55%) of patients who met referral criteria were not seen for genetic counseling. Patients who were diagnosed with endometrial cancer at younger ages, who had primary surgery at our institution, or who met more than one referral criteria were more likely to be seen for genetic counseling. Conclusions: Endometrial cancer patients who met referral criteria and attended genetic counseling comprised a population enriched for Lynch syndrome. This approach allowed Lynch syndrome evaluation resources to be targeted to a population of patients that is high risk and interested in the information. The referral rate of at-risk patients needs to be improved, and allocating resources towards this goal could increase the identification of Lynch syndrome while avoiding some of the pitfalls of universal screening. [Copyright &y& Elsevier]

Background: The incidence of complex atypical hyperplasia and early-stage endometrioid endometrial cancer is increasing, in part owing to the epidemic of obesity, which is a risk factor tightly linked to the development of endometrial hyperplasia and cancer. The standard upfront treatment for complex atypical hyperplasia and early-stage endometrial cancer is hysterectomy. However, nonsurgical treatment of early-stage endometrial neoplasia may be necessary owing to medical comorbidities precluding surgery or desired future fertility.Objective: This study aimed to evaluate the efficacy of the levonorgestrel intrauterine device to treat complex atypical hyperplasia and grade 1 endometrioid endometrial carcinoma.Study Design: A single-institution, single-arm, phase II study of the levonorgestrel intrauterine device (52 mg levonorgestrel, Mirena) was conducted in patients with complex atypical hyperplasia or grade 1 endometrioid endometrial cancer. The primary endpoint was pathologic response rate at 12 months, including complete or partial response. Quality of life and toxicity were assessed. Molecular analyses for proliferation markers, hormone-regulated genes, and wingless-related integration site pathway activation were performed at baseline and 3 months.Results: A total of 57 patients were treated (21 endometrial cancer, 36 complex atypical hyperplasia). The median age was 48.0 years, and the median body mass index was 45.5 kg/m2. Of the 47 evaluable patients, 12-month response rate was 83% (90% credible interval, 72.7-90.3)-37 were complete responders (8 endometrial cancer; 29 complex atypical hyperplasia), 2 were partial responders (2 endometrial cancer), 3 had stable disease (2 endometrial cancer; 1 complex atypical hyperplasia), and 5 had progressive disease (3 endometrial cancer; 2 complex atypical hyperplasia). After stratification for histology, the response rate was 90.6% for complex atypical hyperplasia and 66.7% for grade 1 endometrioid endometrial cancer. Notably, 4 patients (9.5%) experienced relapse after the initial response. Adverse events were mild, primarily irregular bleeding and cramping. Quality of life was not negatively affected. At 3 months, exogenous progesterone effect was present in 96.9% of responders (31 of 32) vs 25% of nonresponders (2 of 8) (P=.001). Nonresponders had higher baseline proliferation (Ki67) and lower dickkopf homolog 3 gene expression than responders (P=.023 and P=.030). Nonresponders had significantly different changes in secreted frizzled-related protein 1, frizzled class receptor 8, and retinaldehyde dehydrogenase 2 compared with responders.Conclusion: The levonorgestrel intrauterine device has a substantial activity in complex atypical hyperplasia and grade 1 endometrioid endometrial cancer, with a modest proportion demonstrating upfront progesterone resistance. Potential biomarkers were identified that may correlate with resistance to therapy; further exploration is warranted. [ABSTRACT FROM AUTHOR]

Objective: To assess efficacy of the levonorgestrel-releasing intrauterine device (LNG-IUD) for treatment of complex atypical hyperplasia or low-grade endometrial cancer.Methods: This retrospective case series included all patients treated with the LNG-IUD for complex atypical hyperplasia or early-grade endometrial cancer from January 2003 to June 2013. Response rates were calculated and the association of response with clinicopathologic factors, including age, body mass index, and uterine size, was determined.Results: Forty-six patients diagnosed with complex atypical hyperplasia or early-grade endometrial cancer were treated with the LNG-IUD. Of 32 evaluable patients at the 6-month time point, 15 had complex atypical hyperplasia (47%), nine had G1 endometrial cancer (28%), and eight had grade 2 endometrial cancer (25%). Overall response rate was 75% (95% CI 57-89) at 6 months; 80% (95% CI 52-96) in complex atypical hyperplasia, 67% (95% CI 30-93) in grade 1 endometrial cancer, and 75% (CI 35-97) in grade 2 endometrial cancer. Of the clinicopathologic features evaluated, there was a trend toward the association of lack of exogenous progesterone effect in the pathology specimen with nonresponse to the IUD (P=.05). Median uterine diameter was 1.3 cm larger in women who did not respond to the IUD (P=.04).Conclusion: Levonorgestrel-releasing IUD therapy for the conservative treatment of complex atypical hyperplasia or early-grade endometrial cancer resulted in return to normal histology in a majority of patients. [ABSTRACT FROM AUTHOR]

Objective: Obesity and estrogen are strong risk factors for endometrial cancer (EC). Whereas diabetes also increases the risk, little is known about related insulin resistance (IR). The purpose of this study was to determine the prevalence of IR in newly diagnosed EC patients. Study Design: EC patients from a large, metropolitan county were prospectively enrolled from 2005 to 2008. Fasting serum was analyzed for glucose and insulin. IR was defined as a history of diabetes or a quantitative insulin sensitivity check index (QUICKI) (1/[log fasting insulin + log fasting glucose]) value of less than 0.357. Results: Among 99 patients, diabetes was present in 30, and an abnormal QUICKI was found in 36 additional patients. Increased risk of IR was significantly associated with higher body mass index (P < .001), lower socioeconomic status (P = .007), and nulliparity (P = .029). Conclusion: IR was highly prevalent in endometrial cancer patients, including nonobese women. Better characterization of metabolic risks in addition to obesity may provide avenues for targeted cancer prevention in the future. [ABSTRACT FROM AUTHOR]

Our pilot clinical study of EphA2 inhibitor (dasatinib) plus paclitaxel and carboplatin showed interesting clinical activity in endometrial cancer with manageable toxicity. However, the underlying mechanisms of dasatinib resistance in uterine cancer are unknown. Here, we investigated potential mechanisms underlying resistance to EphA2 inhibitors in uterine cancer and examined the anti-tumor activity of EphA2 inhibitors alone and in combination with a MEK inhibitor. We evaluated the antitumor activity of EphA2 inhibitors plus a MEK inhibitor using in vitro and in vivo orthotopic models of uterine cancer. EphA2 inhibitor induced MAPK in dasatinib-resistant uterine cancer cells (HEC-1A and Ishikawa) and BRAF/CRAF heterodimerization in HEC-1A cells. EphA2 inhibitor and trametinib significantly increased apoptosis in cancer cells resistant to EphA2 inhibitors compared with controls (p < 0.01). An in vivo study with the orthotopic HEC-1A model showed significantly greater antitumor response to combination treatment compared with dasatinib alone (p < 0.01). Combination treatment increased EphrinA1 and BIM along with decreased pMAPK, Jagged 1, and c-MYC expression in dasatinib-resistant cells. In addition, Spearman analysis using the TCGA data revealed that upregulation of EphA2 was significantly correlated with JAG1, MYC , NOTCH1 , NOTCH3 and HES1 expression (p < 0.001, r = 0.25–0.43). Specifically, MAP3K15 and the NOTCH family genes were significantly related to poor clinical outcome in patients with uterine cancer. These findings indicate that the MAPK pathway is activated in dasatinib-resistant uterine cancer cells and that EphrinA1-mediated MEK inhibition overcomes dasatinib resistance. Dual targeting of both EphA2 and MEK, combined with chemotherapy, should be considered for future clinical development. • Our pilot clinical study of dasatinib showed clinical activity in endometrial cancer. • The underlying mechanisms of dasatinib resistance in uterine cancer are unknown. • MAPK pathway is activated in dasatinib-resistant uterine cancer cells. • MEK inhibition overcomes dasatinib resistance in uterine cancer. • Dual targeting of EphA2 and MEK should be considered for future clinical development. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Obesity-associated hyperestrogenism and hyperinsulinemia contribute significantly to the pathogenesis of endometrial cancer. We recently demonstrated that metformin, a drug long used for treatment of type 2 diabetes, attenuates both insulin- and estrogen-mediated proliferative signaling in the obese rat endometrium. In this study, we sought to identify tissue biomarkers that may prove clinically useful to predict tissue response for both prevention and therapeutic studies. We identified CGRRF1 (cell growth regulator with ring finger domain 1) as a novel metformin-responsive gene and characterized its possible role in endometrial cancer prevention. Methods: CGRRF1 mRNA expression was evaluated by RT-qPCR in the endometrium of obese and lean rats, and also in normal and malignant human endometrium. CGRRF1 levels were genetically manipulated in endometrial cancer cells, and its effects on proliferation and apoptosis were evaluated by MTT and Western blot. Results: CGRRF1 is significantly induced by metformin treatment in the obese rat endometrium. In vitro studies demonstrate that overexpression of CGRRF1 inhibits endometrial cancer cell proliferation. Analysis of human endometrial tumors reveals that CGRRF1 expression is significantly lower in hyperplasia, Grade 1, Grade 2, Grade 3, MMMT, and UPSC endometrial tumors compared to normal human endometrium (p<0.05), suggesting that loss of CGRRF1 is associated with the presence of disease. Conclusion: CGRRF1 represents a novel, reproducible tissue marker of metformin response in the obese endometrium. Furthermore, our preliminary data suggests that up-regulation of CGRRF1 expression may prove clinically useful in the prevention or treatment of endometrial cancer. [Copyright &y& Elsevier]